Fused heterocycles as inhibitors of glutamate racemase(MURI)

ABSTRACT

This invention relates to novel compounds having formula: (I) or (II) and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of  H. pylori  infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C § 371 ofInternational Application No. PCT/GB2004/003464 (filed Aug. 12, 2004)which claims priority under 35 U.S.C. § 111 to Application No.60/495,615 filed on Aug. 15, 2003, the specification of which isincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to novel fused heterocycles, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods for the treatment andprevention of various diseases caused by Helicobacter pylori (H. pylori)infection.

BACKGROUND OF THE INVENTION

Helicobacter pylori (H. pylori) is a highly motile, S-shaped,microaerophilic gram-negative bacterium that colonizes in the stomach.H. pylori infection is widespread with seroprevalence in the developedworld between 30-60%. Infection with the bacterium is usually contractedduring childhood and patients remain infected for life unless treated.H. pylori infection has been shown to result in the development ofgastritis, peptic ulcer, and mucosa-associated lymphoid tissue (MALT)lymphoma and has been linked to gastric adenocarcinoma (Go, M. F. and D.T. Smoot, Helicobacter pylori, gastric MALT lymphoma, and adenocarcinomaof the stomach Seminars in Gastrointestinal Disease, 2000, 11(3): p.134-141). Eradication of H. pylori infection is currently achieved usingcombination therapy of antimicrobial and antisecretory agents(Malfertheiner, P., A. Leodolter, and U. Peitz, Cure of Helicobacterpylori-associated ulcer disease through eradication Bailliere's BestPractice and Research in Clinical Gastroenterology, 2000, 14(1): p.119-132). However, compliance to these therapies is compromised due toadverse side effects and cumbersome dosing regimens. In addition,increasing prevalence of H. pylori strains resistant to existingantimicrobial therapies threatens to limit the use of these treatments(Qureshi, W. A. and D. Y. Graham, Antibiotic-resistant H. pyloriinfection and its treatment. Current Pharmaceutical Design, 2000, 6(15):p. 1537-1544). Given these considerations, a therapy for H. pyloriinfection would be a novel antimicrobial monotherapy that is selectivefor H. pylori eradication. The selectivity attribute is expected to aidin minimizing side effects on gut flora.

H. pylori, like all Gram positive and Gram negative bacteria, utilize acell wall comprised of crosslinked peptidoglycan units to maintain shapeand resist high osmotic pressure potentials. Bacterial cell wallbiosynthesis is a validated target for antimicrobial activity;cephalosphorins, penicillins and glycopeptides are antimicrobial agents,which block cell wall biosynthesis (Walsh, C., Molecular mechanisms thatconfer antibacterial resistance. Nature, 2000, 406: p. 775-781). Cellwall biosynthesis requires the enzyme MurI, a glutamate racemase, andtherefore this enzyme is essential for bacterial viability (Doublet, P.,et al., The murI gene of Escherichia coli is an essential gene thatencodes a glutamate racemase activity. Journal of Bacteriology, 1993,175(10): p. 2970-9).

The present invention describes compounds, which specifically inhibit H.pylori MurI, compositions of such compounds and methods of use. Thecompounds disclosed herein represent a valuable contribution to thedevelopment of selective therapies directed to diseases resulting fromH. pylori infection.

SUMMARY OF THE INVENTION

A compound having the structural formula (I):

wherein,

A is N or CR^(I);

R^(I) is, independently at each instance, H, halogen, cyano, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted amino, optionally substituted carboxy, optionallysubstituted carbonyl, optionally substituted carbamide, optionallysubstituted sulfide, optionally substituted sulphone, optionallysubstituted sulfoxide, optionally substituted sulphamide;

R^(II) is, independently at each instance, H, halogen, cyano, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted amino, optionally substituted carboxy, optionallysubstituted carbonyl, optionally substituted carbamide, optionallysubstituted sulfide, optionally substituted sulphone, optionallysubstituted sulfoxide, optionally substituted sulphamide;

R² is H, optionally substituted alkyl, optionally substitutedalkylcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted cycloalkynyl, optionallysubstituted aryl, optionally substituted alkoxy, optionally substitutedamino, or optionally substituted heterocycle;

R³ is a monocyclic or bicyclic, saturated or unsaturated, ring systemcomprising 0, 1, 2 or 3 heteroatoms independently selected from N, O, orS, the ring being substituted by 0, 1, 2 or 3 substituents selected from═O, halogen, —OR^(a), C₁₋₆alkyl, C₁₋₆haloalkyl, —CN, nitro,—S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(—O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), N═NR^(a), aminocarbonyl, phenyl, benzyl; orR³ is represented by -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-O—R⁵,—R⁵—R⁵—R⁵—OR⁵;

R⁴ is a monocyclic or bicyclic, saturated or unsaturated, ring system,or a vicinal-fused derivative thereof, which may contain from 5 to 12,preferably 5 to 10, ring atoms, 0, 1, 2, 3 or 4 of which are heteroatomsindependently selected from N, O, or S, the ring system beingsubstituted by 0, 1, 2 or 3 substituents selected from B(OH)₂, vicinal—OCH₂CH₂O—, vicinal —OC₁₋₂haloalkylO—, vicinal —OCH₂O—, vicinal—CH₂OCH₂O—, ═O, halogen, —R^(b)OR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR⁸,—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), —NHC(═O)OR^(a), N═NR^(a), NO₂,—C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)_(n)R^(a)),—C(═O)NR^(a)(R^(b)Het), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)),—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a)), aminocarbonyl, phenyl, benzyl; or R⁴ isrepresented by —(CH₂)_(n)R⁵-Het, —(CH₂)_(n)R^(d), -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-OR⁵, R⁵—R⁵, or —R⁵—OR⁵; or R⁴ is represented byC₁₋₆alkyl, —NC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ wherein the C₁₋₆alkyl,—NC₁₋₆alkyl, —N(C₁₋₆alkyl) are substituted by 0, 1 or 2 substituentsselected from R^(a), OR^(a), halogen or phenyl wherein R⁴ is not—CH₂)_(z)CH₃, —(CH₂)_(z)CH₂OH, —(CH₂)_(z)CO₂H, or —(CH₂)_(z)CO₂C₁₋₆alkylwherein z is 1,2,3,4,5, or 6;

R⁵ is independently at each instance, phenyl substituted by 0, 1, 2, or3 groups selected from halogen, C₁₋₆haloalkyl, —OC₁₋₆haloalkyl,C₁₋₆allyl, —CN, nitro, —OR^(a), —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—R^(b)OR^(a), —SR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),—C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR^(a)R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a),—C(═O)R^(b)NR^(a)R^(a), —C(═NOR^(a))R^(a), —C(═NCN)R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);

R^(a) is, independently at each instance, H, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(b) is, independently at each instance, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(c) is C₁₋₆alkyl, C₁₋₄haloalkyl, phenyl or benzyl;

R^(d) is phenyl substituted by 0, 1 or 2 groups selected from —CN,halogen, nitro, C₁₋₆alkyl, C₁₋₄haloalkyl, —OH, —OR^(c), —NR^(a)R^(a),—S(═O)_(n)R^(c), —C(═O)NR^(a)R^(a), —C(═O)OR^(a), —NR^(a)C(═O)R^(a),—OC(═O)R^(a), B(OH)₂, vicinyl —OCH₂CH₂O—, vicinyl —OC₁₋₂haloalkylO—,vicinyl —OCH₂O—, vicinyl —CH₂OCH₂O—, phenyl, benzyl and a 5- or6-membered ring, saturated or unsaturated heterocycle containing 1, 2, 3or 4 heteroatoms independently selected from N, O, or S;

m is 1, 2 or 3;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The invention also encompasses stereoisomers, enantiomers, invivo-hydrolysable precursors and pharmaceutically-acceptable salts ofcompounds of formula I, pharmaceutical compositions and formulationscontaining them, methods of using them to treat diseases and conditionseither alone or in combination with other therapeutically-activecompounds or substances, processes and intermediates used to preparethem, uses of them as medicaments, uses of them in the manufacture ofmedicaments and uses of them for diagnostic and analytic purposes.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides novel compoundshaving structural formula (I):

wherein,

A is N or CR^(I);

R^(I) is, independently at each instance, H, halogen, cyano, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted amino, optionally substituted carboxy, optionallysubstituted carbonyl, optionally substituted carbamide, optionallysubstituted sulfide, optionally substituted sulphone, optionallysubstituted sulfoxide, optionally substituted sulphamide;

R^(II) is, independently at each instance, H, halogen, cyano, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted amino, optionally substituted carboxy, optionallysubstituted carbonyl, optionally substituted carbamide, optionallysubstituted sulfide, optionally substituted sulphone, optionallysubstituted sulfoxide, optionally substituted sulphamide;

R² is H, optionally substituted alkyl, optionally substitutedalkylcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted cycloalkynyl, optionallysubstituted aryl, optionally substituted alkoxy, optionally substitutedamino, or optionally substituted heterocycle;

R³ is a monocyclic or bicyclic, saturated or unsaturated, ring systemcomprising 0, 1, 2 or 3 heteroatoms independently selected from N, O, orS, the ring being substituted by 0, 1, 2 or 3 substituents selected from═O, halogen, —OR^(a), C₁₋₆alkyl, C₁₋₆haloalkyl, —CN, nitro,—S(═O)_(n)R^(c), —O(CH₂)_(m)Het —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(═O)NR^(a)R^(b), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), N═NR^(a), aminocarbonyl, phenyl, benzyl; orR³ is represented by -Het, -Het-Het, R⁵, —R⁵-Het, -Het-R⁵, -Het-O—R⁵,—R⁵—R, —R⁵—OR⁵;

R⁴ is a monocyclic or bicyclic, saturated or unsaturated, ring system,or a vicinal-fused derivative thereof, which may contain from 5 to 12,preferably 5 to 10, ring atoms, 0, 1, 2, 3 or 4 of which are heteroatomsindependently selected from N, O, or S, the ring system beingsubstituted by 0, 1, 2 or 3 substituents selected from B(OH)₂, vicinal—OCH₂CH₂O—, vicinal —OC₁₋₂haloalkylO—, vicinal —OCH₂O—, vicinal—CH₂OCH₂O—, ═O, halogen, —R^(b)OR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R³, —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), —NHC(═O)OR^(a), N═NR^(a), NO₂,—C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)R^(a)),—C(═O)NR^(a)(R^(b)Het), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)),—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a)), aminocarbonyl, phenyl, benzyl; or R⁴ isrepresented by —(CH₂)_(n)R⁵-Het, —(CH₂)_(n)R^(d), -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-OR⁵, R⁵—R⁵, or —R⁵—OR⁵; or R⁴ is represented byC₁₋₆alkyl, —NC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ wherein the C₁₋₆alkyl,—NC₁₋₆alkyl, —N(C₁₋₆alkyl) are substituted by 0, 1 or 2 substituentsselected from R^(a), OR^(a), halogen or phenyl wherein R⁴ is not—(CH₂)_(z)CH₃, —(CH₂)_(z)CH₂OH, —(CH₂)_(z)CO₂H, or—(CH₂)_(z)CO₂C₁₋₆alkyl wherein z is 1,2,3,4,5, or 6;

R⁵ is independently at each instance, phenyl substituted by 0, 1, 2, or3 groups selected from halogen, C₁₋₆haloalkyl, —OC₁₋₆haloalkyl,C₁₋₆alkyl, —CN, nitro, —OR^(a), —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR⁶,—R^(b)OR^(a), —SR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),—C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR^(a)R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), C(═O)R^(a),—C(═O)R^(b)NR^(a)R^(a), —C(═NOR^(a))R^(a), —C(═NCN)R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);

R^(a) is, independently at each instance, H, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(b) is, independently at each instance, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(c) is C₁₋₆alkyl, C₁₋₄haloalkyl, phenyl or benzyl;

R^(d) is phenyl substituted by 0, 1 or 2 groups selected from —CN,halogen, nitro, C₁₋₆alkyl, C₁₋₄haloalkyl, —OH, —OR^(c), —NR^(a)R^(a),—S(═O)R^(c), —C(═O)NR^(a)R^(a), —C(═O)OR^(a), —NR^(a)C(═O)R^(a),—OC(═O)R^(a), B(OH)₂, vicinyl —OCH₂CH₂O—, vicinyl —OC₁₋₂haloalkylO—,vicinyl —OCH₂O—, vicinyl —CH₂OCH₂O—, phenyl, benzyl and a 5- or6-membered ring, saturated or unsaturated heterocycle containing 1, 2, 3or 4 heteroatoms independently selected from N, O, or S;

m is 1, 2 or 3;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

A is N or CR²⁰ wherein R²⁰ is H, halogen, cyano, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkynyl, —OC₀₋₄alkyl, —N(C₀₋₄alkyl)(C₀₋₄alkyl).

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

R^(I) is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

R^(II) is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

R² is C₁₋₆alkylC₃₋₆cycloalkyl or —C₁₋₆-alkyl wherein either isoptionally substituted with 0, 1, 2 or 3 substituents selected from Het,S(═O)_(n)R^(c), —S(═O)_(n)NR^(a)R^(a) halogen, —CN, —OR^(a),—NR^(a)R^(a), —C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a),—OC(═O)C₁₋₄alkyl, or —NR^(a)C(O)C₁₋₄alkyl and n is 0, 1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

R³ is selected from formulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n−1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

R⁴ is selected from formulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

A is N or CR²⁰ wherein R²⁰ is H, halogen, cyano, C₁₋₆allyl, C₁₋₆alkenyl,C₁₋₆alkynyl, —OC₀₋₄alkyl, —N(C₀₋₄alkyl)(C₀₋₄alkyl);

R^(I) is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₁₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2;

R^(II) is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2;

R² is —CH₂CH₂CH₃, —CH₂-cyclopropyl, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂F,—CH₂-cyclobutyl, —CH₂C(CH₃)₃, —CH₂CH₂CH(CH₃)₂, —CH₂CF₃,—CH₂-methylphenyl, —CH₂-phenol, —CH₂-(3,5-dimethylisoxazol-4-yl),—CH₂—S-phenyl, —CH₂-phenylcarboxyl, or —CH₂SCF₃;

R³ is selected from formulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (II), and X is C or N; and Z is O or S, whereinR¹⁰ is at any position on the ring and R¹⁰ and R¹¹ are independently ateach instance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —(═O)_(n)R^(c) and n=1 or 2;

R⁴ is selected from formulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).

In an additional embodiment the present invention provides compoundshaving the formula (I) as recited above wherein:

-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-(dethylamino)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[3-amino-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;-   8-{[5-chloro-1-(methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;-   8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-[1-methyl-4-(methylsulfonyl)-1H-pyrrol-2-yl]-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;-   5-[8-{[5-chloro-1-(methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile.

In a further embodiment the present invention provides compounds havingthe formula (II) as recited above wherein:

wherein,

R′ is H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl;

R″ is independently at each instance H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl;

y is 1 or 2;

R² is H, optionally substituted alkyl, optionally substitutedalkylcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted cycloalkynyl, optionallysubstituted aryl, optionally substituted alkoxy, optionally substitutedamino, or optionally substituted heterocycle;

R³ is a monocyclic or bicyclic, saturated or unsaturated, ring systemcomprising 0, 1, 2 or 3 heteroatoms independently selected from N, O, orS, the ring being substituted by 0, 1, 2 or 3 substituents selected from═O, halogen, —OR^(a), C₁₋₆alkyl, C₁₋₆haloalkyl, —CN, nitro,—S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), N═NR^(a), aminocarbonyl, phenyl, benzyl; orR³ is represented by -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-O—R⁵,—R⁵—R⁵, —R⁵—OR⁵;

R⁴ is a monocyclic or bicyclic, saturated or unsaturated, ring system,or a vicinal-fused derivative thereof, which may contain from 5 to 12,preferably 5 to 10, ring atoms, 0, 1, 2, 3 or 4 of which are heteroatomsindependently selected from N, O, or S, the ring system beingsubstituted by 0, 1, 2 or 3 substituents selected from B(OH)₂, vicinal—OCH₂CH₂O—, vicinal —OC₁₋₂haloalkylO—, vicinal —OCH₂O—, vicinal—CH₂OCH₂O—, ═O, halogen, —R^(b)OR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), —NHC(═O)OR^(a), N═NR^(a), NO₂,—C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)_(n)R^(a)),—C(═O)NR^(a)(R^(b)Het), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)),—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a)), aminocarbonyl, phenyl, benzyl; or R⁴ isrepresented by —(CH₂)_(n)R⁵-Het, —(CH₂)_(n)R^(d), -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-OR⁵, R⁵—R⁵, or —R⁵—OR⁵; or R⁴ is represented byC₁₋₆alkyl, —NC₁₋₆alkyl, or —N(C₁₋₆allyl)₂ wherein the C₁₋₆alkyl,—NC₁₋₆alkyl, —N(C₁₋₆alkyl) are substituted by 0, 1 or 2 substituentsselected from R^(a), OR^(a), halogen or phenyl wherein R⁴ is not—CH₂)_(z)CH₃, —(CH₂)_(z)CH₂OH, —(CH₂)_(z)CO₂H, or —(CH₂)_(z)CO₂C₁₋₆alkylwherein z is 1,2,3,4,5, or 6;

R⁵ is independently at each instance, phenyl substituted by 0, 1, 2, or3 groups selected from halogen, C₁₋₆haloalkyl, —OC₁₋₆haloalkyl,C₁₋₆alkyl, —CN, nitro, —OR^(a), —S(═O)_(n)R^(c), —O(CH₂)_(m)Het,—O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—R^(b)OR^(a), —SR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),—C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR^(a)R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a),—C(═O)R^(b)NR^(a)R^(a), —C(═NOR^(a))R^(a), —C(═NCN)R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);

R^(a) is, independently at each instance, H, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(b) is, independently at each instance, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S;

R^(c) is C₁₋₆alkyl, C₁₋₄haloalkyl, phenyl or benzyl;

R^(d) is phenyl substituted by 0, 1 or 2 groups selected from —CN,halogen, nitro, C₁₋₆alkyl, C₁₋₄haloalkyl, —OH, —OR^(c), —NR^(a)R^(a),—S(═O)_(n)R^(c), —C(═O)NR^(a)R^(a), —C(═O)OR^(a), —NR^(a)C(═O)R^(a),—OC(═O)R^(a), B(OH)₂, vicinyl —OCH₂CH₂O—, vicinyl —OC₁₋₂haloalkylO—,vicinyl —OCH₂O—, vicinyl —CH₂OCH₂O—, phenyl, benzyl and a 5- or6-membered ring, saturated or unsaturated heterocycle containing 1, 2, 3or 4 heteroatoms independently selected from N, O, or S;

m is 1, 2 or 3;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R′ is H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl.

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R″ is independently at each instance H, C₁₋₆allyl, C₁₋₆alkenyl,C₁₋₆alkynyl.

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R² is C₁₋₆alkylC₃₋₆cycloalkyl or —C₁₋₁₂alkyl wherein either isoptionally substituted with 0, 1, 2 or 3 substituents selected from Het,S(═O)_(n)R^(c), —S(═O)_(n)NR^(a)R^(a) halogen, —CN, —OR^(a),—NR^(a)R^(a), —C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a),—OC(═O)C₁₋₄alkyl, or —NR^(a)C(═O)C₁₋₄alkyl and n is 0, 1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R³ is selected from formulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(O)_(n)R^(c) and n=1 or 2.

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R⁴ is selected from formulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

R′ is H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl;

R″ is independently at each instance H, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyl;

y is 1;

R² is —CH₂CH₂CH₃, —CH₂-cyclopropyl, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂F,—CH₂-cyclobutyl, —CH₂C(CH₃)₃, —CH₂CH₂CH(CH₃)₂, —CH₂CF₃,—CH₂-methylphenyl, —CH₂-phenol, —CH₂-(3,5-dimethylisoxazol-4-yl),—CH₂—S-phenyl, —CH₂-phenylcarboxyl, or —CH₂SCF₃;

R³ is selected from formulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄allyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n=1 or 2;

R⁴ is selected from formulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).

In an additional embodiment the present invention provides compoundshaving the formula (II) as recited above wherein:

-   5-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo    [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile;5-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-2-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[(3R)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[(3S)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;-   5-[9-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-2,3,4,6,7,9-hexahydropyrazolo[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl]-1-methyl-1H-pyrrole-3-carbonitrile.

In an additional embodiment the present invention provides compoundshaving the formula (I) or (II) as recited above for use as a medicament.

In an additional embodiment the present invention provides the use of acompound having the formula (I) or (II) in the manufacture of amedicament for the treatment or prophylaxis of disorders associated withH. pylori infection.

In an additional embodiment the present invention provides a method forthe treatment of infections associated with H. pylori comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound as defined in formula (I) or (II).

In an additional embodiment the present invention provides a method forthe prophylaxis treatment of infections associated with H. pyloricomprising administering to a host in need of such treatment atherapeutically effective amount of a compound as defined in formula (I)or (II).

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of infections associated with H. pyloricomprising administering to a host in need of such treatment atherapeutically effective amount of a compound as defined in formula (I)or (II).

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound as defined in formula(I) or (II) together with at least one pharmaceutically acceptablecarrier, diluent or excipent.

Definitions

The definitions set forth in this section are intended to clarify termsused throughout this application. The term “herein” means the entireapplication.

As used in this application, the term “optionally substituted,” as usedherein, means that substitution is optional and therefore it is possiblefor the designated atom to be unsubstituted. In the event a substitutionis desired then such substitution means that any number of hydrogens onthe designated atom is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. Forexample when a substituent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced.

When any variable (e.g., R¹, R⁴, R^(a), R^(e) etc.) occurs more than onetime in any constituent or formula for a compound, its definition ateach occurrence is independent of its definition at every otheroccurrence. Thus, for example, if a group is shown to be substitutedwith 0-3 R¹, then said group may optionally be substituted with 0,1, 2or 3 R¹ groups and R^(e) at each occurrence is selected independentlyfrom the definition of R^(e). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.When required, separation of the racemic material can be achieved bymethods known in the art. Many geometric isomers of olefins, C—N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein “acyl” refers to groups of the of the general formula—C(═O)—R, wherein R is hydrogen, hydrocarbyl radical, amino or alkoxy.Examples of acyl groups include, but are not limited to acetyl,propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.

As used herein the term “amine” or “amino” refers to groups of thegeneral formula —NRR′, wherein R and R′ are independently selected fromhydrogen or a hydrocarbyl radical.

As used herein “aromatic” refers to hydrocarbyl groups having one ormore polyunsaturated carbon rings having aromatic character, (e.g., 4n+2delocalized electrons) and comprising up to about 14 carbon atoms.

As used herein, “allyl” or “alkylene” used alone or as a suffix orprefix, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 12 carbon atomsor if a specified number of carbon atoms is provided then that specificnumber would be intended. For example “C₁₋₆ alkyl” denotes alkyl having1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. As used herein, “C₁₋₃ alkyl”,whether a terminal substituent or an alkylene group linking twosubstituents, is understood to specifically include both branched andstraight-chain methyl, ethyl, and propyl.

As used herein, “alkenyl” or “alkenylene” is intended to include from 2to 12 hydrocarbon atoms of either a straight or branched configurationwith one or more carbon-carbon double bonds that may occur at any stablepoint along the chain. Examples of “C₃₋₆alkenyl” include, but are notlimited to, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl.

As used herein, “alkynyl” or “alkynylene” is intended to include from 2to 12 hydrocarbon chains of either a straight or branched configurationwith one or more carbon-carbon triple bonds that may occur at any stablepoint along the chain. Examples of alkynyl include but are not limitedto ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl.

As used herein, “alkoxy” or “alkyloxy” represents an alkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy,n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy.Similarly, “alkylthio” or “thioalkoxy” represent an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge.

As used herein, the term “aryl” is intended to mean aromatic groupsincluding both monocyclic aromatic groups comprising 6 carbon atoms andpolycyclic aromatic groups comprising up to about 14 carbon atoms.

As used herein the term “cycloalkyl” is intended to include saturatedring groups, having the specified number of carbon atoms. For example,“C₃₋₆ cycloalkyl” denotes such groups as cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein the term “alkylcycloalkyl” is intended to mean an alkylattached to the formula atom and also attached to a cycloalkyl. Examplesof alkylcycloalkyl include, but are not limited to cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl,cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl,cycloheptylpropyl.

As used herein “cycloalkenyl” refers to ring-containing hydrocarbylgroups having at least one carbon-carbon double bond in the ring, andhaving from 3 to 12 carbons atoms.

As used herein “cycloalkynyl” refers to ring-containing hydrocarbylgroups having at least one carbon-carbon triple bond in the ring, andhaving from 7 to 12 carbons atoms.

As used herein, “electronically neutral” refers to a stable compoundhaving a no charge.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate,tosylate, benezensulfonate, and the like.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, andheptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy,2,2,2-trifluoroethoxy, and the like. “Haloalkylthio” is intended to meana haloalkyl group as defined above with the indicated number of carbonatoms attached through a sulphur bridge.

As used herein, the term “Het” is intended to mean a 5 or 6 member ring,saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O, or S, and substituted by 0, 1, 2 or 3substituents selected from halogen, C₁₋₄alkyl, —S(═O)_(n)R^(c),—C(═O)R^(a), or —S(═O)₂NR^(a)R^(a), vicinal —OCH₂CH₂O—, vicinal—OC₁₋₂haloalkylO—, vicinal —OCH₂O—, or vicinal —CH₂OCH₂O—, ═O, halogen,cyano, —R^(b)OR^(a), —R^(b)SR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, nitro, —OH, 'NHR^(a), —NR^(a) ₂, —NHC(═O)R^(a),N═NR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR²R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);

As used herein, the term “heterocycle” or “heterocyclic” refers to aring-containing monovalent and divalent structures having one or moreheteroatoms, independently selected from N, O and S, as part of the ringstructure and comprising from 3 to 20 atoms in the rings. Heterocyclicgroups may be saturated or unsaturated, containing one or more doublebonds, and heterocyclic groups may contain more that one ring. Theheterocyclic rings described herein may be substituted on carbon or on aheteroatom atom if the resulting compound is stable. If specificallynoted, nitrogen in the heterocycle may optionally be quaternized. It isunderstood that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azetidine, aziridine, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl,imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxirane, oxazolidinylperimidinyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidine,pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, thiophane, thiotetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,thiamine, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl.

In addition to the polycyclic heterocycles described above, heterocyclicor heterocycle compounds include polycyclic heterocyclic moietieswherein the ring fusion between two or more rings comprises more thanone bond common to both rings and more than two atoms common to bothrings. Examples of such bridged heterocycles include quinuclidine,diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

As used herein, “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts-of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, maleic,tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers thatrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Formulations

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

An effective amount of a compound of the present invention for use intherapy of infection is an amount sufficient to symptomatically relievein a warm-blooded animal, particularly a human the symptoms ofinfection, to slow the progression of infection, or to reduce inpatients with symptoms of infection the risk of getting worse.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds aniallowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. Examples of such acidaddition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate,camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium, lithium andpotassium salts, alkaline earth metal salts such as aluminum, calciumand magnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; aralkylhalides like benzyl bromide and others. Non-toxicphysiologically-acceptable salts are preferred, although other salts arealso useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which-the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

The term composition is intended to include the formulation of theactive component or a pharmaceutically acceptable salt with apharmaceutically acceptable carrier. For example this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition is divided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Such methods include, but are not limited to,those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described herein. The reactions are performedin solvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents, which are compatiblewith the reaction conditions, will be readily apparent to one skilled inthe art and alternate methods must then be used.

Examples of such processes are illustrated below:

In an aspect of the invention, intermediate compounds of formula Ib maybe formed by reacting compounds of formula Ia with R²—X in a solventsuch as DMSO and a base such as K₂CO₃ with heat as set forth below:

An intermediate compound of formula Ic may be formed by reacting acompound of Formula Ib with NH₂NH₂H₂O in ethanol and refluxed asfollows:

Intermediate compound of Formula Id may be formed by reacting compoundsof formula Ic with R³—CHO in methanol as follows:

Intermediate compounds of formula Ie may by formed by reacting compoundsof formula Id with R⁴—CHO and reflux in DMF with piperdine as follows:

Compounds of formula If may by formed by reacting compounds of formulaIe with POCl₃, 3-nitro-1,2,4 triazole in pyridine at 70 C followed byamine (HORNH₂) as set forth below:

Compounds of formula I may by formed by reacting compounds of formula Ifwith methanesulfonyl chloride as set forth below:

In an aspect of the invention, intermediate compounds of formula IIa maybe formed from reaction of compounds of formula Ie with P₂S₅ inpyridine.

Compounds of formula II (A is N) may by formed by reacting compounds offormula IIa with an appropriate acylhydrazide, mercury chloride inacetonitrile with heat as set forth below:

Compounds of formula II (A is CH) may also by formed by reactingcompounds of formula IIa with an appropriate aminoketone, mercurychloride in acetonitrile with heat as set forth below:

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows: Bocdenotes t-butoxycarbonyl, Cbz denotes benzyloxycarbonyl, DCM denotesmethylene chloride, DIPEA denotes diisopropylethylamine, DMF denotesN,N-dimethylformamide, DMSO denotes dimethyl sulfoxide, Et₂O denotesdiethyl ether, EtOAc denotes ethyl acetate, TFA denotes trifluoroaceticacid, THF denotes tetrahydrofuran. Solvent mixture compositions aregiven as volume percentages or volume ratios. In cases where the NMRspectrum is complex, only diagnostic signals are reported.

Other terms used in the Examples are defined as follows: atm. denotesatmospheric pressure, equiv. denotes equivalent(s), h denotes hour(s),T_(b) denotes bath temperature, HPLC denotes high performance liquidchromatography, min denotes minutes, NMR denotes nuclear magneticresonance, psi denotes pounds per square inch.

-   (i) temperatures are given in degrees Celsius (° C.); unless    otherwise stated, operations were carried out at room or ambient    temperature, that is, at a temperature in the range of 18-25° C.;-   (ii) organic solutions were dried over anhydrous magnesium sulfate    or sodium sulfate; evaporation of solvent was carried out using a    rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30    mm Hg) with a bath temperature of up to 60° C.;-   (iii) chromatography means flash chromatography on silica gel or by    FlashMaster™ II by Jones Chromatography using Isolute columns; thin    layer chromatography (TLC) was carried out on silica gel plates;-   (iv) in general, the course of reactions was followed by TLC or    analytical HPLC and reaction times are given for illustration only;-   (v) melting points are uncorrected and (dec) indicates    decomposition;-   (vi) final products had satisfactory proton nuclear magnetic    resonance (NMR) spectra;-   (vii) when given, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    tetramethylsilane (TMS) as an internal standard, determined at 300    or 500 MHz using deuterated chloroform (CDCl₃) or DMSO-d₆ or CD₃OD    as solvent; conventional abbreviations for signal shape are used;    for AB spectra the directly observed shifts are reported; coupling    constants (J) are given in Hz; Ar designates an aromatic proton when    such an assignment is made;-   (viii) reduced pressures are given as absolute pressures in pascals    (Pa); elevated pressures are given as gauge pressures in bars;-   (ix) solvent ratios are given in volume:volume (v/v) terms; and-   (x) Mass spectra (MS) were run using an automated system with    atmospheric pressure electrospray ionization (ESI). Generally, only    spectra where parent masses are observed are reported. The lowest    mass major ion is reported for molecules where isotope splitting    results in multiple mass spectral peaks (for example when chlorine    is present).

The invention will now be illustrated by the following non-limitingexamples.

Example 15-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile

(a) 6-Chloro-1-cyclopropylmethylpyrimidine-2,4[1H,3H]dione

6-Chlorouracil I (49.64 g, 0.34 mol; Lancaster) was dissolved inanhydrous DMSO (375 mL) and treated with solid K₂CO₃ (23.46 g, 0.17 mol)under nitrogen. The resulting white suspension was heated to ca. 80-90°C. and kept at this temperature for 2¼ h. Foaming was observed as thetemperature increased, then the reaction mixture became mostly clear.Cyclopropylmethyl bromide (65 g, 0.48 mol) was added neat via syringe,resulting in a white fluffy precipitate. This was followed by acatalytic amount of KI (2.88 g, 0.017 mol). The reaction mixture washeated for 19 hr, becoming mostly homogenous, then turbid with whitegranular precipitate, and eventually orange as the reaction progressed,remaining heterogeneous. 375 mL 1 N NaOH (aq) was added to the hotreaction mixture, causing it to darken and clear. The heat was removedand the reaction mixture allowed to cool to room temperature whilestirring. It was washed with 4×125 mL toluene and the organic washingsdiscarded. The aqueous phase was brought to pH 2-3 by the addition ofca. 100 mL conc. HCl (aq.). 50 mL water was added, and precipitationbegan after about one hour at room temperature; cooling in ice completedthe crystallization. The yellow-green solid was collected by filtrationand washed with very cold ether to remove most of the color, then driedunder vacuum. Yield: 29.37 g (43%) of a light yellow solid.

(b) 1-cyclopropylmethyl-6-hydrazinopyrimidine-2,4[1H,3H]dione

6-Chloro-1-cyclopropylmethyluracil (24.34 g, 0.12 mol) was suspended inabsolute ethanol (245 mL) under nitrogen. Anhydrous hydrazine (11.69 g,0.36 mol) was added via syringe in excess, resulting in a clear-yellowsolution. The reaction mixture was heated at 80-85° C. for one hour;bright yellow crystals began forming within minutes of the applicationof heat. The reaction mixture was cooled to room temperature and then inan ice bath, and the crude product collected by filtration. N₂H₄×HCl wasremoved by triturating with cold water to give the product as a paleyellow solid, 20.47 g (86%). Mp 221° C. (dec).

(c) 6-chloroquinoline-4-carbaldehyde[3-(cyclopropylmethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4yl]hydrazone

To a suspension of1-cyclopropylmethyl-6-hydrazinopyrimidine-2,4[1H,3H]dione (5.05 g) inmethanol (75 mL) was added 6-chloroquinoline 4-carbaldehyde (5.30 g).After stirring overnight, the reaction was filtered, yielding a yellowsolid (10 g).

(d)5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cycopropylmethyl)-4,6-dioxo4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile (2.5 g) inDMF (50 mL) were added 6-chloroquinoline-4-carbaldehyde[3-(cyclopropylmethyl)-2,6-ioxo-1,2,3,6-tetrahydropyrimidin-4-yl]hydrazone(5.66 g) and piperdine (2 mL). After stirring overnight at T_(b)=75° C.,the reaction was diluted with ethyl acetate and water. The organicsolution was collected, washed with saturated NaHCO₃ and brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified byFlashMaster™ yielding 8.63 g of white solid. Mass: 486 (M+H)⁺.

(e)5-{2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-[(2-hydroxyethyl)amino]-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-{2-[(6-chloroquinolin-4-yl)methyl]-7-cyclopropylmethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile(0.42 g) in pyridine (5 mL) were added 4-chlorophenylphosphorodichloridate (0.5 mL) and 3-nitro-1,2,4 triazole (0.15 g).After heating (T_(b)=50° C.) for 3 h, the reaction was diluted withethyl acetate. The organic solution was washed with saturated NaHCO₃ andbrine, dried (Na₂SO₄), filtered and concentrated. The residue wasdissolved in THF (10 mL) and ethanolamine (1.0 mL). After 3 h, thereaction was concentrated. This residue was purified by flashchromatography using a FlashMaster™ yielding 0.22 g, ES (M+H)⁺=529.

(5)5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-{2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-[(2-hydroxyethyl)amino]-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-a]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile(0.20 g) in CH₂Cl₂ (5 mL) were added triethylamine (0.30 mL) andmethanesulfonlyl chloride (0.15 mL). After 30 min, the reaction wasconcentrated and purified by reverse phase HPLC with a Gilson system (54mg). 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.50 (m, 4H) 1.39 (m, 1H) 3.32(s, 3H) 3.93 (m, 6H) 5.70 (q, J=15.82 Hz, 2H) 6.59 (d, J=1.70 Hz, 1H)6.78 (d, J=4.33 Hz, 1H) 7.26 (d, J=1.70 Hz, 1H) 7.71 (dd, J=9.04, 2.26Hz, 1H) 7.88 (d, J=2.07 Hz, 1H) 8.11 (d, J=9.04 Hz, 1H) 8.82 (d, J=4.33Hz, 1H); ES (M+H)⁺=512.

Following the method of Example 1 and using the appropriate aldehydesand hydrazinopyrimidine-2,4[1H,3H]dione, Examples 2 to 7 were made byreaction of methanesulfonlyl chloride and the appropriate aminoalcoholprecursor.

Example 25-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.98 (t, J=6.31 Hz, 6H) 1.28 (m,3H) 2.34 (m, 1H) 3.29 (s, 2H) 3.82 (d, J=7.54 Hz, 1H) 3.94 (m, 4H) 5.69(m, 2H) 6.59 (d, J=1.70 Hz, 1H) 6.75 (d, J=4.33 Hz, 1H) 7.27 (d, J==1.70Hz, 1H) 7.71 (dd, J=8.95, 2.17 Hz, 1H) 7.91 (d, J=2.07 Hz, 1H) 8.11 (d,J=9.04 Hz, 1H) 8.81 (d, J=4.52 Hz, 1H); ES (M+H)⁺514.

Example 35-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.50 (m, 4H) 1.41 (m, 4H) 3.33 (d,J=23.55 Hz, 3H) 3.57 (m, 1H) 3.87 (m, 2H) 4.11 (m, 1H) 4.43 (m, 1H) 5.70(m, 2H) 6.59 (d, J=1.70 Hz, 1H) 6.79 (dd, J=8.57, 4.43 Hz, 1H) 7.28 (m,1H) 7.71 (m, 1H) 7.89 (dd, J=8.38, 2.17 Hz, 1H) 8.11 (d, J=9.04 Hz, 1H)8.82 (dd, J=4.33, 2.45 Hz, 1H); ES (M+H)⁺525.

Example 45-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-2-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.47 (m, 4H) 1.30 (m, 4H) 3.34 (d,J=18.84 Hz, 3H) 3.51 (s, 2H) 3.94 (m, 3H) 4.33 (m, 1H) 5.74 (m, 1H) 6.59(s, 1H) 6.79 (d, J=4.33 Hz, 1H) 7.33 (m, 1H) 7.73 (s, 1H) 7.88 (s, 1H)8.11 (d, J=9.04 Hz, 1H) 8.82 (d, J=4.52 Hz, 1H); ES (M+H)⁺525.

Example 55-[(3R)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.50 (m, 4H) 1.40 (m, 3H) 1.75 (m,1H), 3.33 (d, J=23.36 Hz, 3H) 3.57 (m, 1H) 3.88 (m, 2H) 4.11 (m, 1H)4.43 (m, 1H) 5.72 (m, 2 H) 6.59 (d, J=1.70 Hz, 1H) 6.79 (dd, J=8.38,4.43 Hz, 1H) 7.28 (m, 1H) 7.71 (m, 1H) 7.89 (dd, J=8.10, 2.07 Hz, 1H)8.11 (d, J=9.04 Hz, 1H) 8.82 (dd, J=4.43, 2.35 Hz, 1H); ES (M+H)⁺525.

Example 65-[(3S)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.50 (m, 4H) 1.41 (m, 3H) 1.77 (m,1H) 3.32 (d, 3H) 3.56 (m, 1H) 3.88 (m, 1H) 4.10 (m, 1H) 4.41 (m, 1H)5.71 (m, 2H) 6.59 (d, J=1.51 Hz, 1H) 6.79 (dd, J=8.29, 4.52 Hz, 1H) 7.28(m, 1H) 7.71 (m, 1H) 7.89 (dd, J=8.10, 2.07 Hz, 1H) 8.11 (d, J=9.23 Hz,1H) 8.82 (dd, J=4.33, 2.45 Hz, 1H); ES (M+H)⁺525.

Example 75-[9-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-2,3,4,6,7,9-hexahydropyrazolo[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl]-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, DMSO-D6) d ppm 0.38 (m, 2H) 1.31 (m, 1H) 1.78 (m, 1H)3.13 (s, 3 H) 3.30 (m, 2H) 3.77 (m, 2H) 5.82 (m, J=16.20 Hz, 1H) 6.72(s, 1H) 6.77 (m, 1H) 7.67 (s, 1H) 7.80 (d, J=9.23 Hz, 1H) 8.05 (d,J=9.04 Hz, 1H) 8.11 (d, J=1.70 Hz, 1H) 8.80 (d, J=4.52 Hz, 1H); ES(M+H)⁺525.

Example 85-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

(a)5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3yl]-1methyl-1H-pyrrole-3-carbonitrile(0.53 g) in pyridine (5 mL) was added P₄S₁₀ (0.52 g). The mixture washeated by microwave at 140° C. for 100 minutes. The mixture was dilutedwith water and ethyl acetate. The organic solution was collected, washedwith saturated NaHCO₃ and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography using aFlashMaster™ yielding 0.44 g.

(b)5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-[2-[(6-chloroquinolinyl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.14 g) in acetonitrile (5 mL) and formichydrazide (80 mg) was added mercury(II) chloride (160 mg). Afterstirring overnight at rt, the reaction was warmed (T_(b)=70 C). After 5h with heat, the reaction was filtered through a celite bed andconcentrated. The residue was purified by flash chromatography using aFlashMaster™ yielding 44 mg, 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.57(m, 4H) 1.48 (m, J=10.93 Hz, 1H) 3.45 (s, 3H) 4.15 (t, J=6.59 Hz, 2H)5.86 (m, 2H) 6.68 (d, J=1.70 Hz, 1H) 6.83 (d, J=4.52 Hz, 1H) 7.40 (d,J=1.70 Hz, 1H) 7.72 (dd, J=8.95, 2.17 Hz, 1H) 7.88 (d, J=2.07 Hz, 1H)8.13 (d, J=8.85 Hz, 1H) 8.84 (d, J=4.33 Hz, 1H) 8.93 (s, 1H);

ES M+H⁺=510.

Example 95-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a suspension of5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(0.12 g) in acetonitrile (3 mL) were added acetic hydrazide (50 mg) andmercury chloride (0.13 g). The reaction was stirred at rt for 1 h andthen heated by microwave at 100° C. for 30 min. The reaction wasconcentrated, redissolved in ethyl acetate and water, and filteredthrough a celite bed. The organic solution was collected, washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography using a FlashMaster™ yielding 119 mg ofa white foam, 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.56 (m, 4H) 1.47 (s,1H) 2.90 (s, 3H) 3.43 (s, 3H) 4.09 (m, 2H) 5.86 (m, 2H) 6.65 (d, J=1.70Hz, 1H) 6.81 (d, J=4.52 Hz, 1H) 7.38 (d, J=1.51 Hz, 1H) 7.72 (dd,J=8.95, 2.17 Hz, 1H) 7.88 (d, J=2.07 Hz, 1H) 8.12 (d, J=9.04 Hz, 1H)8.83 (d, J=4.33 Hz, 1H); ES M+H⁺=523.

Example 105-[8-[(6-chloroquinolin-4-yl)methyl]-6-cyclopropylmethyl)-3-(dimethylamino)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

(a)5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-hydrazino-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(0.24 g) in THF (5 mL) were added hydrazine hydrate (0.30 mL) andmercury chloride (0.30 g). After 4 h, a second addition of hydrazinehydrate (0.20 mL) and mercury chloride (0.30 g) was done. After stirringovernight, the mixture was diluted with water and ethyl acetate. Themixture was then filtered through a celite bed. The organic solution wascollected, washed with saturated NaHCO₃ and brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography using a FlashMaster™ yielding 0.18 g.

(b)5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-(dimethylamino)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-hydrazino-6-oxo-6,7-dihydro-2H-pyrazolo[3,4d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(0.13 g) in dioxane (3 mL) was added phosgene iminium chloride (0.12 g).The reaction was heated by microwave at 100° C. for 5 min. The mixturewas concentrated and purified by RP-HPLC yielding 94 mg of yellow foam,1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.56 (m, 4H) 1.44 (m, J=7.35 Hz,1H) 3.06 (s, 6H) 3.46 (s, 3H) 4.10 (m, 2H) 5.84 (m, 2H) 6.62 (d, J=1.70Hz, 1H) 6.81 (d, J=4.52 Hz, 1H) 7.35 (d, J=1.70 Hz, 1H) 7.71 (dd,J=9.04, 2.07 Hz, 1H) 7.87 (d, J=2.07 Hz, 1H) 8.12 (d, J=9.04 Hz, 1H)8.83 (d, J=4.52 Hz, 1H); ES M+H⁺=553.

Example 115-[3-amino-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

To a solution of5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-hydrazino-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(0.13 g) in dioxane (3 mL) was added cyanogen bromide (0.15 mL). Thereaction was heated by microwave at 100° C. for 5 min. The mixture wasconcentrated and purified by HPLC yielding 27 mg of yellow foam, 1H NMR(300 MHz, CHLOROFORM-D) d ppm 0.56 (m, 4 H) 1.44 (m, 1H) 3.7 (s, 3H)3.94 (m, 2H) 5.84 (m, 2H) 6.54 (d, 1H) 6.86 (m, 1H) 7.71 (m, 2H) 7.87(m, 1H) 8.12 (m, 1H) 8.85 (m, 1H); ES M+H⁺=525.

Example 125-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(130 mg, 0.26 mmol) was dissolved in 5 mL of anhydrous acetonitrile.2-Aminoacetaldehyde dimethyl acetal (55 mg, 0.52 mmol, 2.0 eq.) wasadded and the solution stirred 5 minutes. Mercury(II) chloride (176 mg,0.65 mmol, 2.5 eq.) was added and the mixture heated in the microwavereactor at 130° C. for 70 minutes. The resulting dark solution wasdiluted in 30 mL water and 30 mL dichloromethane and filtered throughcelite to remove the dark precipitate. The celite pad was washedrepeatedly with small amounts of dichloromethane. The organic layer wasdried over sodium sulfate, filtered and concentrated on the rotaryevaporator. The crude product was purified by chromatography on silica(gradient: hexane to ethyl acetate). The resulting product was stillimpure so it was re-purified by chromatography on silica (gradient:dichloromethane to 10% methanol in dichloromethane). The product wasthen recrystallized by dissolving in a minimum of dichloromethane (ca.0.5 mL) followed by addition of six volumes of methanol. Isolated 91 mg(68% yield) ofthe product as small yellow crystals. 1H NMR (300 MHz,CHLOROFORM-D) d ppm 0.55 (m, 4H) 1.48 (m, 1H) 3.36 (s, 3H) 4.15 (m, 2H)5.81 (m, 2H) 6.64 (d, J=1.70 Hz, 1H) 6.76 (d, J=4.33 Hz, 1H) 7.22 (d,J=1.51 Hz, 1H) 7.35 (d, J=1.51 Hz, 1H) 7.69 (m, 2H) 7.91 (d, J=2.07 Hz,1H) 8.08 (d, J=9.04 Hz, 1H) 8.80 (d, J=4.52 Hz, 1H); ES M+H⁺=510.

Following the method of Example 12 and preparing the appropriate amidefollowing Example 1, the following examples were made from1-cyclopropylmethyl-6-hydrazinopyrimidine-2,4[1H,3H]dione.

Example 138-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one

aldehydes: 1(c) 6-chloroquinoline 4-carbaldehyde; 1(d)1-methyl-1H-imidazole-5-carbaldehyde

1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.55 (s, 4H) 1.51 (s, 1H) 3.51 (s,3H) 4.18 (m, 2H) 5.82 (m, 2H) 6.77 (d, J=4.33 Hz, 1H) 7.22 (d, 1H) 7.26(d, 1H) 7.70 (m, 2H) 7.76 (d, J=1.51 Hz, 1H) 7.94 (d, J=2.07 Hz, 1H)8.11 (d, J=9.04 Hz, 1H) 8.81 (d, J=4.52 Hz, 1 H); ES (M+H)⁺485

Example 148-{[5-chloro-1-(methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one

aldehydes: 1(c) 5-chloro-1-(methylsulfonyl)-1H-indole-3-carbaldehyde;1(d) 1-methyl-1H-imidazole-5-carbaldehyde 1H NMR (300 MHz, CHLOROFORM-D)d ppm 0.60 (m, 4H) 1.52 (m, 1H) 3.13 (s, 3H) 3.51 (s, 3H) 4.19 (d,J=7.16 Hz, 2H) 5.53 (m, J=48.79 Hz, 2H) 7.18 (s, 1H) 7.23 (d, J=1.51 Hz,1H) 7.34 (m, 2H) 7.45 (d, J=1.51 Hz, 1 H) 7.75 (m, 3H); ES (M+H)⁺552

Example 158-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-[1-methyl-4-(methylsulfonyl)-1H-pyrrol-2-yl]-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one

aldehydes: 1(c) 6-chloroquinoline 4-carbaldehyde; 1(d)1-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carbaldehyde

1H NMR (300 MHz, DMSO-D6) d ppm 0.48 (s, 3H) 1.41 (s, 1H) 3.09 (s, 3H)3.32 (m, 3H) 4.04 (s, 1H) 6.03 (m, 1H) 6.81 (d, J=1.51 Hz, 1H) 6.88 (d,J=4.71 Hz, 1H) 7.26 (d, J=1.32 Hz, 1H) 7.70 (d, J=1.51 Hz, 1H) 7.83 (m,2H) 8.07 (d, J=9.04 Hz, 1H) 8.16 (s, 1H) 8.81 (d, J=4.52 Hz, 1H); ES(M+H)⁺563

Example 165-[8-{[5-chloro-1-methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

aldehydes: 1(c) 5-chloro-1-(methylsulfonyl)-1H-indole-3-carbaldehyde;1(d) 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile

1H NMR (300 MHz, DMSO-D6) d ppm 0.52 (m, 4H) 1.41 (s, 1H) 3.30 (m, 4H)3.46 (s, 3 H) 4.05 (s, 2H) 5.61 (m, J=31.65 Hz, 2H) 7.05 (d, J=1.70 Hz,1H) 7.22 (d, J=1.51 Hz, 1H) 7.32 (s, 1H) 7.41 (dd, J=8.85, 2.07 Hz, 1H)7.55 (d, J=2.07 Hz, 1H) 7.80 (m, 2H) 7.94 (d, J=1.51 Hz, 1H); ES(M+H)⁺576

Example 175-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

a)5-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile

5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(0.5g, 1.0 mmol) was dissolved in 10 mL anhydrous THF. Anhydrous ammoniain methanol (20 mL of 2M solution) was added, followed by mercury (II)chloride (410 mg, 1.5 mmol, 1.5 eq). The mixture was heated to 60° C.for 48 h. Volatiles were evaporated and the residue dissolved in 100 mLethyl acetate, 50 mL dichloromethane, and 100 mL water. The organiclayer was washed with water (100 mL) and dried over sodium sulfate. Theresidue was purified by chromatography on silica (gradient:dichloromethane to 10% methanol in dichloromethane), yielding 232 mg(48%) of the product as a yellow solid. ES M+H⁺=485.

b)5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

5-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile(75 mg, 0.15 mmol) was dissolved in 1.5 mL anhydrous DMF with 30 mg DBU.Chloroacetone (28 mg, 0.3 mmol, 2.0 eq.) was added and the resultingsolution heated in the microwave for 90 minutes at 125° C. Two additioneq. chloroacetone were added, and the reaction returned to the microwaveand heated an additional 90 minutes at 125° C. The reaction mixture wasdiluted with 50 mL. water and 50 mL ethyl acetate. The aqueous layer waswashed 3×50 mL with ethyl acetate. The combined organic fractions werewashed with 50 mL brine and dried over sodium sulfate. The crude productwas purified by chromatography on silica (gradient: dichloromethane to10% methanol in dichloromethane), followed by reverse phase HPLC using40% aqueous acetonitrile, yielding 20 mg product. 1H NMR (300 MHz,CHLOROFORM-D) d ppm 0.55 (m, 4H) 1.48 (m, 1H) 2.27 (d, J=0.94 Hz, 3H)3.42 (s, 3 H) 4.13 (m, 2H) 5.82 (m, 2H) 6.62 (dd, J=4.52, 1.88 Hz, 1H)6.76 (d, J=4.33 Hz, 1H) 7.36 (d, J=1.51 Hz, 1H) 7.44 (d, J=1.13 Hz, 1H)7.70 (dd, J=9.04, 2.26 Hz, 1H) 7.90 (d, J=2.26 Hz, 1H) 8.10 (m, 1H) 8.81(d, J=4.52 Hz, 1H); ES M+H⁺=524.

The compounds of the present invention have utility for the preventionand treatment of H. pylori infection. Methods of treatment target theprevention of cell wall biosynthesis through the MurI enzyme. Compoundsthat inhibit MurI activity control the production of cell wallbiosynthesis. The inhibition of MurI will inhibit growth of H. pyloriand will reduce or prevent the diseases resulting from H. pyloriinfection such as peptic ulcers, gastritis and MALT lymphoma Thecompounds of the present invention have utility for the prevention andtreatment of such disorders.

Compounds of the present invention have been shown to inhibit MurI, asdetermined by glutamate racemase activity assay described herein.Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit MurI. These would be provided in commercial kits comprising acompound of this invention.

As used herein “rt” denotes room temperature, “ug” denotes microgram,“mg” denotes milligram, “g” denotes gram, “uL” denotes microliter, “mL”denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “uM”denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm”denotes nanometer, “DMSO” denotes dimethyl sulfoxide, “DTT” denotesdithiothreitol, “EDTA” denotes ethylenediaminetetraacetate,

Glutamate Racemase Activity Assay:

Glutamate racemase (MurI) activity was assayed by measuring theconversion of glutamate from the D to the L enantiomer. This reactionwas coupled to the reduction of NAD⁺ to NADH by L-glutamatedehydrogenase (LGDH). LGDH from bovine liver was obtained as alyophilized powder (Roche #197734) and dissolved in buffer containing 10mM Tris (Sigma #T-6791), pH 7.5, 0.1 mM EDTA (Fisher #BP118-500) and 50%(weight/volume) glycerol (Sigma #G-9012). The assay mixture consisted of100 mM Tris-HCl, pH 8.0, 10 mM β-NAD (Sigma #N-1511), 5 mM DTT (Sigma#D-5545), 0.03% PEG (mw 8000, Sigma #P-5413), 0.03 mg/mL BSA (Pierce#23210), 15 U/mL LGDH, D-glutamate (40 μM, Fluka #49460), and purifiedMurI (50 nM or 1 uM). The assay was performed in 96-well blackmicrotiter plates (Greiner #XN2-9511) in a final assay volume of 100 μL.Compounds were prepared as 20 mM stock solutions in dimethyl sulfoxide(DMSO, Sigma #D-5879) and serial dilutions were prepared from thesesolutions using DMSO, 2 μL of which were added to the wells. Activity atroom temperature was measured by monitoring the increase in fluorescenceusing a TECAN Ultra plate reader with 340 nm excitation and 465 nmemission filters. The compounds described have a measured IC₅₀ in thisassay of less than 400 μM.

1. A compound having the structural formula (I):

wherein, A is N or CR^(I); R^(I) is, independently at each instance, H,halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, amino, carboxy,alkylcarbonyl, alkylcarbamide, alkylsulfide, alkylsulphone,alkylsulfoxide, sulphamide; R^(II) is, independently at each instance,H, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, amino,carboxy, alkylcarbonyl, alkylcarbamide, alkylsulfide, alkylsulphone,sulfoxide, sulphamide; R² is H, alkyl, wherein said alkyl is optionallysubstituted with 0, 1, 2 or 3 substituents selected from heterocycle,S(═O)_(n)R^(C), —S(═O)_(n)NR^(a)R^(a) halogen, —CN, —OR^(a),—NR^(a)R^(a), —C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a),—OC(═O)C₁₋₄alkyl, or —NR^(a)C(═O)C₁₋₄alkyl, alkylcycloalkyl, whereinsaid alkylcycloalkyl is optionally substituted with 0, 1, 2 or 3substituents selected from heterocycle, S(═O)_(n)R^(c),—S(═O)_(n)NR^(a)R^(a) halogen, —CN, OR^(a), —NR^(a)R^(a), —C(═O)OR^(a),—C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl, or—NR^(a)C(═O)C₁₋₄alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, alkoxy, amino, or heterocycle; R³ is a monocyclic orbicyclic, saturated or unsaturated, ring system comprising 0, 1, 2 or 3heteroatoms independently selected from N, O, or S, the ring beingsubstituted by 0, 1, 2 or 3 substituents selected from ═O, halogen,—OR^(a), C₁₋₆-alkyl, C₁₋₆haloalkyl, —CN, nitro, —S(═O)_(n)R^(c),—O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a),—O(CH₂)_(m)C(═O)OR^(a), —O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a),—S(CH₂)_(m)Het, —S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), N═NR^(a), aminocarbonyl, phenyl, benzyl; orR³ is represented by -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-O—R⁵,—R⁵—R⁵, —R⁵—OR⁵; R⁴ is a monocyclic or bicyclic, saturated orunsaturated, ring system, or a vicinal-fused derivative thereof, whichmay contain from 5 to 12 ring atoms, 0, 1, 2, 3 or 4 of which areheteroatoms independently selected from N, O, or S, the ring systembeing substituted by 0, 1, 2 or 3 substituents selected from B(OH)₂,vicinal —OCH₂CH₂O—, vicinal —OC₁₋₂haloalkylO—, vicinal —OCH₂O—, vicinal—CH₂OCH₂O—, ═O, halogen, —R^(b)OR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), —NHC(═O)OR^(a), N═NR^(a), NO₂,—C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O) NR^(a)(R^(b)S(═O)R^(a)),—C(═O)NR^(a)(R^(b)Het), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)),—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a)), aminocarbonyl, phenyl, benzyl; or R⁴ isrepresented by —(CH₂)_(n)R⁵-Het, —(CH₂)_(n)R^(d), -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-OR⁵, R⁵—R⁵, or —R⁵—OR⁵; or R⁴ is represented byC₁₋₆alkyl, —NC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ wherein the C₁₋₆alkyl,—NC₁₋₆alkyl, —N(C₁₋₆alkyl) are substituted by 0, 1 or 2 substituentsselected from R^(a), OR^(a), halogen or phenyl wherein R⁴ is not—(CH₂)_(z)CH₃, —(CH₂)_(z)CH₂OH, —(CH₂)_(z)CO₂H, or—(CH₂)_(z)CO₂C₁₋₆alkyl wherein z is 1,2,3,4,5, or 6; R⁵ is independentlyat each instance, phenyl substituted by 0, 1, 2, or 3 groups selectedfrom halogen, C₁₋₆haloalkyl, —OC₁₋₆haloalkyl, C₁₋₆alkyl, —CN, nitro,—OR^(a), —S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—R^(b)OR^(a), —SR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),—C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR^(a)R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a),—C(═O)R^(b)NR^(a)R^(a), —C(═NOR^(a))R^(a), —C(═NCN)R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);R^(a) is, independently at each instance, H, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S; R^(b) is, independently at each instance,C₁₋₆alkyl, —C(═O)C₁₋₄alkyl, C₁₋₄haloalkyl, phenyl, benzyl, or 5 or6-memebered ring, saturated or unsaturated heterocycle containing 1,2,3,or 4 heteroatoms independently selected from N, O or S; R^(c) isC₁₋₆alkyl, C₁₋₄haloalkyl, phenyl or benzyl; R^(d) is phenyl substitutedby 0, 1 or 2 groups selected from —CN, halogen, nitro, C₁₋₆alkyl,C₁₋₄haloalkyl, —OH, —OR^(c), —NR^(a)R^(a), —S(═O)_(n)R^(c),—C(═O)NR^(a)R^(a), —C(═O)OR^(a), —NR^(a)C(═O)R^(a), —OC(═O)R^(a),B(OH)₂, vicinyl —OCH₂CH₂O—, vicinyl —OC₁₋₂haloalkylO—, vicinyl —OCH₂O—,vicinyl —CH₂OCH₂O—, phenyl, benzyl and a 5- or 6-membered ring,saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O, or S; m is 1, 2 or 3; n is 0, 1 or 2;or a pharmaceutically acceptable salt thereof.
 2. A compound as recitedin claim 1 wherein: A is N or CR²⁰ wherein R²⁰ is H, halogen, cyano,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl).
 3. A compound as recited in claim 1 wherein:R^(I) is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or
 2. 4. A compound asrecited in claim 1 wherein: R^(II) is H, halogen, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, S(═O)_(n)C₁₋₄alkyl,—S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl, —N(C₀₋₄alkyl)(C₀₋₄alkyl),—C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or —C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl)where n is 0, 1 or
 2. 5. A compound as recited in claim 1 wherein: R³ isselected from formulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n=1 or
 2. 6. A compound asrecited in claim 1 wherein: R⁴ is selected from formulas (a) to (z) or(aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).
 7. A compound as recited in claim 1wherein: A is N or CR²⁰ wherein R²⁰ is H, halogen, cyano, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, —OC₀₋₄alkyl, —N(C₀₋₄alkyl)(C₀₋₄alkyl); R^(I)is H, halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2; R^(II) is H,halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,S(═O)_(n)C₁₋₄alkyl, —S(═O)_(n)N(C₁₋₄alkyl)_(n), —OC₀₋₄alkyl,—N(C₀₋₄alkyl)(C₀₋₄alkyl), —C(═O)OC₁₋₄alkyl, —C(═O) C₀₋₄alkyl, or—C(═O)N(C₀₋₄alkyl)(C₀₋₄alkyl) where n is 0, 1 or 2; R² is —CH₂CH₂CH₃,—CH₂-cyclopropyl, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂F, —CH₂-cyclobutyl,—CH₂C(CH₃)₃, —CH₂CH₂CH(CH₃)₂, —CH₂CF₃, —CH₂-methylphenyl, —CH₂-phenol,—CH₂-(3,5-dimethylisoxazol-4-yl), —CH₂—S-phenyl, —CH₂-phenylcarboxyl, or—CH₂SCF₃; R³ is selected from formulas (i), (ii), (iii) or (iv) setforth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (II), and X is C or N; and Z is O or S, whereinR¹⁰ is at any position on the ring and R¹⁰ and R¹¹ are independently ateach instance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n=1 or 2; R⁴ is selected fromformulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).
 8. A compound of claim 1 selected from:5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-(dimethylamino)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-carbonitrile;5-[3-amino-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;8-{[5-chloro-1-(methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-9-(1-methyl-1H-imidazol-5-yl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-9-[1-methyl-4-(methylsulfonyl)-1H-pyrrol-2-yl]-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one;5-[8-{[5-chloro-1-(methylsulfonyl)-1H-indol-3-yl]methyl}-6-(cyclopropylmethyl)-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile.
 9. A compound having the structural formula(II):

wherein, R′ is H, alkyl, alkenyl, alkynyl; R″ is independently at eachinstance H, alkyl, alkenyl, alkynyl; y is 1 or 2; R² is H, alkyl,wherein said alkyl is optionally substituted with 0, 1, 2 or 3substituents selected from heterocycle, S(═O)_(n)R^(c),—S(═O)_(n)NR^(a)R^(a) halogen, —CN, —OR^(a), —NR^(a)R^(a), —C(═O)OR^(a),—C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl, or—NR^(a)C(═O)C₁₋₄alkyl, alkylcycloalkyl, wherein said alkylcycloalkyl isoptionally substituted with 0, 1, 2 or 3 substituents selected fromheterocycle, S(═O)_(n)R^(c), —S(═O)_(n)NR^(a)R^(a) halogen, —CN,—OR^(a), —NR^(a)R^(a), —C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a),—OC(═O)C₁₋₄alkyl, or —NR^(a)C(═O)C₁₋₄alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkoxy, amino, orheterocycle; R³ is a monocyclic or bicyclic, saturated or unsaturated,ring system comprising 0, 1, 2 or 3 heteroatoms independently selectedfrom N, O, or S, the ring being substituted by 0, 1, 2 or 3 substituentsselected from ═O, halogen, —OR^(a), C₁₋₆alkyl, C₁₋₆haloalkyl, —CN,nitro, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), N═NR^(a), aminocarbonyl, phenyl, benzyl; orR³ is represented by -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-O—R⁵,—R⁵—R⁵, —R⁵—OR⁵; R⁴ is a monocyclic or bicyclic, saturated orunsaturated, ring system, or a vicinal-fused derivative thereof, whichmay contain from 5 to 12 ring atoms, 0, 1, 2, 3 or 4 of which areheteroatoms independently selected from N, O, or S, the ring systembeing substituted by 0, 1, 2 or 3 substituents selected from B(OH)₂,vicinal —OCH₂CH₂O—, vicinal —OC₁₋₂haloalkylO—, vicinal —OCH₂O—, vicinal—CH₂OCH₂O—, ═O, halogen, —R^(b)OR^(a), —SR^(a), —OR^(a), C₁₋₆alkyl,C₁₋₆haloalkyl, —CN, —S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het, —O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—NR^(a)R^(a), —NHC(═O)R^(a), —NHC(═O)OR^(a), N═NR^(a), NO₂,—C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)_(n)R^(a)),C(═O)NR^(a)(R^(b)Het), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a), C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)),—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a)), aminocarbonyl, phenyl, benzyl; or R⁴ isrepresented by —(CH₂)_(n)R⁵-Het, —(CH₂)_(n)R^(d), -Het, -Het-Het, R⁵,—R⁵-Het, -Het-R⁵, -Het-OR⁵, R⁵—R⁵, or —R⁵—OR⁵; or R⁴ is represented byC₁₋₆alkyl, —NC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ wherein the C₁₋₆alkyl,—NC₁₋₆alkyl, —N(C₁₋₆alkyl) are substituted by 0, 1 or 2 substituentsselected from R^(a), OR^(a), halogen or phenyl wherein R⁴ is not—(CH₂)_(z)CH₃, —(CH₂)_(z)CH₂OH, —(CH₂)_(z)CO₂H, or—(CH₂)_(z)CO₂C₁₋₆alkyl wherein z is 1,2,3,4,5, or 6; R⁵ is independentlyat each instance, phenyl substituted by 0, 1, 2, or 3 groups selectedfrom halogen, C₁₋₆haloalkyl, —OC₁₋₆haloalkyl, C₁₋₆alkyl, —CN, nitro,—OR^(a), —S(═O)_(n)R^(c), —O(CH₂)_(m)Het, —O(CH₂)_(m)C(═O)Het,—O(CH₂)_(m)C(═O)NR^(a)R^(a), —O(CH₂)_(m)C(═O)OR^(a),—O(CH₂)_(m)NR^(a)R^(a), —O(CH₂)_(m)OR^(a), —S(CH₂)_(m)Het,—S(CH₂)_(m)C(═O)Het, —S(CH₂)_(m)C(═O)NR^(a)R^(a),—S(CH₂)_(m)C(═O)OR^(a), —S(CH₂)_(m)NR^(a)R^(a), —S(CH₂)_(m)OR^(a),—R^(b)OR^(a), —SR^(a), —C(═O)NR^(a)R^(a), —C(═O)NR^(a)OR^(a),—C(═O)NR^(a)R^(b)NR^(a)R^(a), —C(═O)NR^(a)R^(b)OR^(a),—C(═O)NR^(a)R^(b)S(═O)_(n)R^(a), —C(═O)NR^(a)R^(b)Het, —C(═O)OR^(a),—OC(═O)R^(a), —C(═O)OR^(b)NR^(a)R^(a), —C(═O)R^(a),—C(═O)R^(b)NR^(a)R^(a), —C(═NOR^(a))R^(a), —C(═NCN)R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂R^(a),—S(═O)₂NR^(a)R^(b)C(═O)NR^(a)R^(a), or —S(═O)₂NR^(a)R^(b)C(═O)OR^(a);R^(a) is, independently at each instance, H, C₁₋₆alkyl, —C(═O)C₁₋₄alkyl,C₁₋₄haloalkyl, phenyl, benzyl, or 5 or 6-memebered ring, saturated orunsaturated heterocycle containing 1,2,3, or 4 heteroatoms independentlyselected from N, O or S; R^(b) is, independently at each instance,C₁₋₆alkyl, —C(═O)C₁₋₄alkyl, C₁₋₄haloalkyl, phenyl, benzyl, or 5 or6-memebered ring, saturated or unsaturated heterocycle containing 1,2,3,or 4 heteroatoms independently selected from N, O or S; R^(c) isC₁₋₆alkyl, C₁₋₄haloalkyl, phenyl or benzyl; R^(d) is phenyl substitutedby 0, 1 or 2 groups selected from —CN, halogen, nitro, C₁₋₆alkyl,C₁₋₄haloalkyl, —OH, —OR^(c), —NR^(a)R^(a), —S(═O)_(n)R^(c),—C(═O)NR^(a)R^(a), —C(═O)OR^(a), —NR^(a)C(═O)R^(a), —OC(═O)R^(a),B(OH)₂, vicinyl —OCH₂CH₂O—, vicinyl —OC₁₋₂haloalkylO—, vicinyl —OCH₂O—,vicinyl —CH₂OCH₂O—, phenyl, benzyl and a 5- or 6-membered ring,saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O, or S; m is 1, 2 or 3; n is 0, 1 or 2;or a pharmaceutically acceptable salt thereof.
 10. A compound as recitedin claim 9 wherein: R′ is H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl.
 11. Acompound as recited in claim 9 wherein: R″ is independently at eachinstance H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl.
 12. A compound asrecited in claim 9 wherein: R³ is selected from formulas (i), (ii),(iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),—C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n=1 or
 2. 13. A compound asrecited in claim 9 wherein: R⁴ is selected from formulas (a) to (z) or(aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).
 14. A compound as recited in claim 9wherein: R′ is H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl; R″ isindependently at each instance H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl; yis 1; R² is —(CH₂CH₂CH₃, —CH₂-cyclopropyl, —CH₂CH(CH₃)₂, —(CH₂CH₂CH₂F,—CH₂-cyclobutyl, —CH₂C(CH₃)₃, —(CH₂CH₂CH(CH₃)₂, —CH₂CF₃,—CH₂-methylphenyl, —(CH₂-phenol, —CH₂-(3,5-dimethylisoxazol-4-yl),—CH₂—S-phenyl, —CH₂-phenylcarboxyl, or —CH₂SCF₃; R³ is selected fromformulas (i), (ii), (iii) or (iv) set forth below:

wherein * is the location where (i) or (ii) or (iii) or (iv) is attachedto structural formula (I), and X is C or N; and Z is O or S, wherein R¹⁰is at any position on the ring and R¹⁰ and R¹¹ are independently at eachinstance H, R^(a), halogen, —CN, nitro, OR^(a), CF₃, —NR^(a)R^(a),C(═O)OR^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)C₁₋₄alkyl,—NR^(a)C(═O)C₁₋₄alkyl or —S(═O)_(n)R^(c); and wherein R^(11a) is R^(a),—S(═O)₂NR^(a)R^(a) or —S(═O)_(n)R^(c) and n=1 or 2; R⁴ is selected fromformulas (a) to (z) or (aa) or (ab) set forth below:

wherein * is the location wherein R⁴ is attached to the ring system andwherein wherein R¹², R¹³ and R¹⁴ are each independently represented byH, Het, C₁₋₆alkyl, —CN, —NR^(a)R^(a), -nitro, —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═O)NR^(a)S(═O)₂R^(a), —C(═O)NR^(a)-Het,—C(═O)NR^(a)NR^(a)R^(a), —C(═O)NR^(a)(R^(b)NR^(a)R^(a)),—C(═O)NR^(a)(R^(b)OR^(a)), —C(═O)NR^(a)(R^(b)S(═O)₂R^(a)),—C(═O)NR^(a)R^(b)Het, —C(═O)NR^(a)OR^(a), —C(═O)R^(b)NR^(a)R^(a),—C(═NOR^(a))R^(a), —C(═NCN)R^(a), —C(═O)OR^(a), —C(═O)OR^(b)NR^(a)R^(a),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)R^(a)—SR^(a), ═S, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)S(═O)₂R^(b), —C(═NOR^(a))R^(a), —S(═O)₂R^(a),S(═O)₂NR^(a)R^(a), S(═O)₂NR^(a)(R^(b)C(═O)NR^(a)R^(a)), or—S(═O)₂NR^(a)(R^(b)C(═O)OR^(a).
 15. A compound of claim 1 selected from:5-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile;5-{8-[(6-chloroquinolin-4-yl)methyl]-6-isobutyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl}-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-2-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[(3R)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[(3S)-8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-2,5,6,8-tetrahydro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile;5-[9-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-2,3,4,6,7,9-hexahydropyrazolo[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl]-1-methyl-1H-pyrrole-3-carbonitrile.16. A method for the treatment of infection with H. pylori comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound as defined in claim
 1. 17. Apharmaceutical composition comprising a compound as defined in claim 1together with at least one pharmaceutically acceptable carrier, diluentor excipent.